Project Summary. A fundamental characteristic of alcohol use disorders is the loss of control over alcohol consumption that results in progressively escalating levels of alcohol use and facilitates the progression to alcohol-dependence. Given the comorbidity of alcohol dependence and disorders of affect such as de-pression is extremely high, it has been posited that self-medication of negative affective states contributes to continued excessive alcohol use and relapse. Furthermore, negative affective states produced by chronic alcohol exposure can influence the neurocircuitry of cognitive control systems to perpetuate further excessive alcohol use. Once that degree of dysregulation is reached, components of the dependence cycle serve to facilitate each other in a manner that is extremely deleterious to personal, familial and societal welfare. The principal investigator?s long-term goal is to identify effective therapeutic targets and strategies for the treatment of AUDs. The objective of this renewal application, which is the next step in pursuit of that goal, is to understand the neuroadaptations in dynorphin (DYN) / kappa-opioid receptor (KOR) systems that occur in response to chronic alcohol exposure and contribute to maladaptive behavioral regulation in the form of maladaptive behavioral regulation. The central hypothesis is that the DYN / KOR system becomes progressively dysregulated in a manner that promotes the continued excessive consumption of alcohol and perpetuates the cycle of alcohol dependence. The rationale for the proposed studies is that identification of novel DYN / KOR- related treatment targets will enable the development of effective therapies designed to alleviate maladaptive behavioral regulation produced by dysphoria and alcohol dependence. This hypothesis will be tested by pursuing the following specific aims: Aim #1 evaluates kappa-opioid receptor dysregulation within cortical nuclei during acute withdrawal within working memory and impulse control domains. Aim #2 assesses the role of KORs in amygdalar nuclei in response to non-dependent dysphoria cues and alcohol-dependent withdrawal cue-induced maladaptive behavioral regulation using a combination of pharmacological and inducible genetic approaches. Animal models of self-administration, negative affective-like behavior, working memory and impulse control will serve as functional end-points to systematically investigate the mechanisms that contribute to maladaptive behavioral regulation in AUDs. These specific aims will collectively help to identify important neuroadaptations in DYN / KOR systems that can promote the transition to, and perpetuation of, AUDs and will provide much needed information regarding the influence of DYN / KORs on the neurocircuitry maladaptive behavioral regulation. Such a contribution is significant because it will help develop personalized therapeutic targets to treat AUDs that focus on the removal of maladaptive phenotypes; a strategy that should greatly increase medication compliance and decrease rates of relapse.